Recent clinical evidence has suggested that, contrary to what was previously believed, cells are able to escape breast cancer lesions at stages when invasive disease is not present, but the mechanisms behind this remain largely unknown. These disseminated tumor cells (DTC's) lodge into secondary sites, enter a state of dormancy, escape conventional therapy, and potentially seed future metastases. Because around 90% of cancer patients die from metastatic disease, rather than as a consequence of their primary tumor is it important to develop more efficient targeted therapies for these disseminated tumor cells. The goal of the proposed research plan is to better understand the mechanisms dictating the dissemination of these cells, as well as those controlling cell fate decisions at secondary sites i order to develop more effective therapies for eradicating these populations. Preliminary evidence suggests that the stress-signaling p38/ MAPK pathway may act to restrict an Epithelial to Mesenchymal Transition (EMT) and consequentially early dissemination from pre-malignant lesions. This regulatory mechanism may be lost in ErbB2+ MECs potentially through activated Wnt signaling. This project will investigate (1) how p38/ inhibits EMT and early dissemination in pre-malignant lesions, (2) the mechanism by which ErbB2 acts to inhibit p38/ signaling and (3) whether the EMT program persists in early DTCs and whether p38/ signaling still influences DTC cell fate in target organs. The proposed research plan will provide novel insight into the role of these signaling pathways in early dissemination and cell fate decisions during early stages of breast cancer progression. Completion of these aims will improve our understanding of the biology behind early dissemination, help to identify patients at higher risk of metastatic disease and potentially identify new targeted therapies for residual disease.